Although immunotherapy research to date has focused largely on T cells, there is mounting evidence that tumour-infiltrating B cells and plasma cells (collectively referred to as tumour-infiltrating B lymphocytes (TIL-Bs)) have a crucial, synergistic role in tumour control. In many cancers, TIL-Bs have demonstrated strong predictive and prognostic significance in the context of both standard treatments and immune checkpoint blockade, offering the prospect of new therapeutic opportunities that leverage their unique immunological properties. Drawing insights from autoimmunity, we review the molecular phenotypes, architectural contexts, antigen specificities, effector mechanisms and regulatory pathways relevant to TIL-Bs in human cancer. Although the field is young, the emerging picture is that TIL-Bs promote antitumour immunity through their unique mode of antigen presentation to T cells; their role in assembling and perpetuating immunologically ‘hot’ tumour microenvironments involving T cells, myeloid cells and natural killer cells; and their potential to combat immune editing and tumour heterogeneity through the easing of self-tolerance mechanisms. We end by discussing the most promising approaches to enhance TIL-B responses in concert with other immune cell subsets to extend the reach, potency and durability of cancer immunotherapy. This Review discusses our current understanding of tumour-infiltrating B lymphocytes (TIL-Bs) in human cancers, considering the role of TIL-Bs across the major facets of cancer immunity. The authors also discuss strategies to harness the cell-based and antibody-based effector mechanisms of TIL-Bs to enable a new generation of cancer immunotherapies. 

Tumour-infiltrating B cells: immunological mechanisms, clinical impact and therapeutic opportunities

Regulatory B cells (Bregs) is a term that encompasses all B cells that act to suppress immune responses. Bregs contribute to the maintenance of tolerance, limiting ongoing immune responses and reestablishing immune homeostasis. The important role of Bregs in restraining the pathology associated with exacerbated inflammatory responses in autoimmunity and graft rejection has been consistently demonstrated, while more recent studies have suggested a role for this population in other immune-related conditions, such as infections, allergy, cancer, and chronic metabolic diseases. Initial studies identified IL-10 as the hallmark of Breg function; nevertheless, the past decade has seen the discovery of other molecules utilized by human and murine B cells to regulate immune responses. This new arsenal includes other anti-inflammatory cytokines such IL-35 and TGF-β, as well as cell surface proteins like CD1d and PD-L1. In this review, we examine the main suppressive mechanisms employed by these novel Breg populations. We also discuss recent evidence that helps to unravel previously unknown aspects of the phenotype, development, activation, and function of IL-10-producing Bregs, incorporating an overview on those questions that remain obscure.

/pdf/immunosuppressive-mechanisms-of-regulatory-b-cells-18q8okqdwe.pdf

Immunosuppressive Mechanisms of Regulatory B Cells.

// Weiwei Wang 1 , Xiangliang Yuan 1 , Hui Chen 1 , Guohua Xie 1 , Yanhui Ma 1 , Yingxia Zheng 1 , Yunlan Zhou 1 and Lisong Shen 1 1 Department of Clinical Laboratory, Xinhua Hospital, affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China Correspondence to: Lisong Shen, email: // Keywords : gastric cancer, regulatory B cells, IL-10, TGF-β, regulatory T cells, immune escape Received : January 30, 2015 Accepted : August 23, 2015 Published : September 10, 2015 Abstract Regulatory B cells (Bregs) play a critical role in inflammation and autoimmune disease. We characterized the role of Bregs in the progression of gastric cancer. We detected an increase in Bregs producing IL-10 both in peripheral blood mononuclear cells (PBMCs) and in gastric tumors. Multicolor flow cytometry analysis revealed that a subset of CD19 + CD24 hi CD38 hi B cells produces IL-10. Functional studies indicated that increased Bregs do not inhibit the proliferation of CD3 + T cells or CD4 + helper T cells (Th cells). However, Bregs do suppress the secretion of IFN-γ and TNF-α by CD4 + Th cells. CD19 + CD24 hi CD38 hi Bregs were also found to correlate positively with CD4 + FoxP3 + regulatory T cells (Tregs). Neutralization experiments showed that Bregs convert CD4 + CD25 - effector T cells to CD4 + FoxP3 + Tregs via TGF-β1. Collectively, these findings demonstrate that increased Bregs play a immunosuppressive role in gastric cancer by inhibiting T cells cytokines as well as conversion to Tregs. These results may provide new clues about the underlying mechanisms of immune escape in gastric cancer.

/pdf/cd19-cd24hicd38hibregs-involved-in-downregulate-helper-t-4vi4rvemkz.pdf

CD19+CD24hiCD38hiBregs involved in downregulate helper T cells and upregulate regulatory T cells in gastric cancer.

Advances in understanding of the immune microenvironment have highlighted the role of immunosuppressive T cell, myeloid, dendritic and monocytic sub-populations in inhibition of the anti-tumor immune response. The role of B cells in modulating the immune response to solid tumors as well as lymphoid malignancies is less well understood. Murine models of autoimmune disease have defined B regulatory cell (Breg) subsets with immune suppressive activity, including B cell subsets that express IL-10, and transforming growth factor-β, which can facilitate T regulatory cell recruitment and expansion. Multiple murine tumor models point to the existence of similar immune suppressive B cell sub-populations that can migrate into tumor deposits and acquire an immune suppressive phenotype, which then leads to attenuation of the local anti-tumor immune response. Other murine models of viral or chemically induced skin carcinogenesis have identified a pivotal role for B cells in promoting inflammation and carcinogenesis. While many human solid tumors demonstrate significant B cell infiltration and/or tertiary lymphoid structure formation, the functional properties of tumor-infiltrating B cells and their effects on immunity are poorly understood. Recent successes in early Phase I/II trials using anti-checkpoint inhibitor antibodies such as nivolumab or pidilizumab directed against PD-1 in the setting of Hodgkin's and non-Hodgkin's lymphomas validate the therapeutic utility of reversing B cell-mediated immune suppression. Further studies to define Breg subsets, and mechanisms of suppression, may provide new avenues for modulation of the immune response and meaningful therapeutic intervention in both lymphoid and solid tumors.

Regulatory B cells in anti-tumor immunity

Regulatory B cells (Bregs) are a subset of B cells, which reportedly exert significant immunomodulatory effects through the production of interleukin (IL)‑10, IL‑35 and transforming growth factor‑β Over the last decade, studies have indicated that Bregs function in autoimmune and allergic diseases through antigen‑specific and non‑specific immunoregulatory mechanisms However, only a limited number of reviews have focused on the role of Bregs during infection, particularly their functions in intracellular infections The present review discusses the role of Bregs in infectious diseases in animal models and human studies, and provides an overview of the immunoregulatory mechanisms used by Bregs

/pdf/regulatory-b-cells-in-infectious-disease-review-1l41a1rjjc.pdf

Regulatory B cells in infectious disease (Review)

IL-21 can induce both plasma cells and regulatory B cells. In this article, we demonstrate that untreated HIV patients display CD4 + T cells with enhanced IL-21 expression and high in vivo frequencies of regulatory B cells overexpressing the serine protease granzyme B. Granzyme B–expressing regulatory B cells (GraB cells) cells from HIV patients exhibit increased expression of CD5, CD43, CD86, and CD147 but do not produce IL-10. The main functional characteristic of their regulatory activity is direct granzyme B–dependent degradation of the TCR-ζ–chain, resulting in significantly decreased proliferative T cell responses. Although Th cells from HIV patients secrete IL-21 in a Nef-dependent manner, they barely express CD40L. When culturing such IL-21 + CD40L − Th cells with B cells, the former directly induce B cell differentiation into GraB cells. In contrast, the addition of soluble CD40L multimers to T cell/B cell cultures redirects B cell differentiation toward plasma cells, indicating that CD40L determines the direction of IL-21–dependent B cell differentiation. As proof of principle, we confirmed this mechanism in a patient lacking intact CD40 signaling due to a NEMO mutation. The majority of peripheral B cells from this patient were GraB cells and strongly suppressed T cell proliferation. In conclusion, GraB cells represent potent regulatory B cells in humans that are phenotypically and functionally distinct from B10 cells and occur in early HIV infection. GraB cells may contribute significantly to immune dysfunction in HIV patients, and may also explain ineffective Ab responses after vaccination. The use of soluble CD40L multimers may help to improve vaccination responses in HIV patients.

/pdf/cd4-t-cell-derived-il-21-and-deprivation-of-cd40-signaling-25ga2zmgyd.pdf

CD4+ T Cell–Derived IL-21 and Deprivation of CD40 Signaling Favor the In Vivo Development of Granzyme B–Expressing Regulatory B Cells in HIV Patients

In addition to the impact GzmB has on antigen uptake, the way it cleaves peptides can result in fragments that represent neo-antigens, allowing the establishment of increased immune responses towards such antigens [16,17]. Thus, one reason for The serine protease granzyme B (GzmB) is classically known to be an apoptogenic effector molecule produced by cytotoxic cells including NK cells and CD8+ T lymphocytes [1]. However,a series of further cell types are able to express GzmB, most of them in the absence of perforin.Below them are different antigen-presenting cells (APC) including B cells [2, 3], monocyte derived dendritic cells [4, 5] and plasmacytoid dendritic cells [6, 7]. Meanwhile we know that GzmB contributes to a variety of APC-related functions. GzmB may therefore represent a promising novel target for the improvement of vaccination approaches based on the use of pDC and other dendritic cell types expressing GzmB.

/pdf/granzyme-b-produced-by-plasmacytoid-dendritic-cells-promotes-4y7h1eu4g8.pdf

Granzyme B produced by Plasmacytoid Dendritic Cells Promotes Antigen uptake While Suppressing Premature T cell Activation

Differential expression of serpins may selectively licence distinct granzyme B functions including antigen cross-presentation.

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

Timo Trzaska

Author Tools

Chat about Author

Papers

CD4+ T Cell–Derived IL-21 and Deprivation of CD40 Signaling Favor the In Vivo Development of Granzyme B–Expressing Regulatory B Cells in HIV Patients

Granzyme B produced by Plasmacytoid Dendritic Cells Promotes Antigen uptake While Suppressing Premature T cell Activation

Differential expression of serpins may selectively licence distinct granzyme B functions including antigen cross-presentation.